    Patent Document 1: JP-A 2003-119120    Patent Document 2: JP-A H04-46115    Patent Document 3: JP-A H11-47580    Non-Patent Document 1: “New development of liposome application—toward the development of artificial cells—”, supervised by Kazunari Akiyoshi and Kaoru Tsujii, published by NTS Inc., June 2005
Today, microcapsules have been attempted for various applications such as transdermal absorption formulations, oral formulations, immune adjuvants, artificial red blood cells, artificial platelets, cosmetics, hair growth agents, hair tonics and antibacterial agents, besides drug capsules such as pharmaceuticals. Further, researches using as artificial cell membranes, drug carriers, gene transfer vectors, reaction fields in nanoscale (bioreactors) and the like have actively proceeded, and therefore, a method for producing microcapsules has been demanded which have less environmental load, favorable preservation stability, as well as are easily produced, capable of mass production and have an intended particle diameter.
A liposome, which is a kind of these microcapsules, has a so-called capsule structure in which water-soluble substances are retained in an internal water phase and lipid-soluble substances are retained inside a bilayer membrane. As methods for producing liposomes, many methods including, for example, the Bangham method, an organic solvent injection method and a reverse phase evaporation method have been reported so far. However, any of the methods uses organic solvents harmful to environment and human bodies, and there are few methods for producing liposomes having high retention efficiency of water-soluble substances without using a large quantity of organic solvents.
Today, a method for producing liposomes or microemulsion particles using mechanical shearing force has been proposed as an industrially producing method. The machines to be used are a preliminary disperser and an accurate disperser, and a high-speed rotating disperser may be used as the preliminary disperser and a high-pressure homogenizer may be used as the accurate disperser in many cases. In these methods, there is an advantage that organic solvents are not used, however, it is not suitable for high molecules having low resistance to the shearing, and there is a problem such that an energetic load is large.
Further, there has been disclosed a method in which supercritical carbon dioxide is used for producing liposomes in place of organic solvents (Patent Document 1). A variety of production conditions can be set in this method, and liposomes having an intended particle diameter, structure and the like can be produced relatively easily as compared with conventional methods for producing liposomes. Even if the liposomes incorporated in the target site of a body are in small amounts, a desired effect can be obtained if the encapsulation ratio of substances to be enclosed is high, and therefore, the method is expected as a production method for DDS formulations. In this method, however, there is a need for being subjected to an application of pressure ranging from 50 kg/m3 to 500 kg/m3 at a temperature in the range of 20° C. to 200° C. upon processing, and a preliminary mixing step in which mixing is carried out previously with a homogenizer or the like is required. Therefore, there are problems such that running costs are high, operation steps are prolonged, complicated and involve risk, and the energetic load is large and thus the method is not suitable for industrial production.
Similarly, microemulsion particles as a kind of microcapsules are used in various fields such as cosmetics, pharmaceuticals, agrichemicals, aqueous paints, waxes and foods. As a method for producing such microemulsion particles, there are known a method in which a hydrocarbon oil is added to an aqueous solution of a high HLB nonionic surfactant, and then temperature is raised, a method in which an electrolyte is added to a combination of a lipophilic nonionic surfactant and a specified ionic surfactant, or a combination of a lipophilic nonionic surfactant and an ionic surfactant, and a method in which strong shearing is applied to a fluid mixture containing oils to finely pulverize the emulsion particles (Patent Document 2). These methods involve various problems such as narrow stable temperature ranges. For example, the following is reported. In a case where emulsification is carried out using a high-pressure emulsification apparatus, if the pressure is set at high level, the base temperature rises upon processing and therefore, the stability of emulsion is affected in some cases (for example, Patent Document 3). A method has been proposed in which processing is carried out by ultrasonic irradiation and the like, but it is difficult in production in a large scale using ultrasonic wave.
In liposomes and microemulsion particles used as biologically ingestible materials such as pharmaceuticals, foods and cosmetics, meticulous attention needs to be paid in production and quality control due to their characteristics. At the same time, excellent temporal stability as particles, uniformity in particle diameter and good encapsulation ratio are required. That is, it can be said that a formulation technique capable of easy production needs to be established.
Further, liposomes and microemulsion particles as biologically ingestible materials preferably exert their functions in a living body as their particle diameter is smaller in many cases, and additional microparticulation is required from the viewpoint of stabilization. However, larger energy needs to be used for a substance to be processed in order to make its particle diameter small, and therefore, countermeasures such that processing time is prolonged and the concentration of a surfactant is raised have to be conducted.
An object of the present invention is to solve the problems in view of the above problems, and to provide a method for obtaining a biologically ingestible material having an intended particle diameter with low energy as compared with conventional methods. That is, the present invention provides a method for producing a biologically ingestible material that is safe and less environmental load with energetic efficiency, and furthermore provides a method in which a biologically ingestible material having a uniform particle diameter can be obtained and productivity is high.